Mutations in the Pericentrin (PCNT) Gene Cause Primordial Dwarfism

Anita Rauch; Christian T. Thiel; Detlev Schindler; Ursula Wick; Yanick J. Crow; Arif B. Ekici; Anthonie J. van Essen; Timm O. Goecke; Lihadh Al-Gazali; Krystyna H. Chrzanowska; Christiane Zweier; Han G. Brunner; Kristin Becker; Cynthia J. Curry; Bruno Dallapiccola; Koenraad Devriendt; Arnd Dörfler; Esther Kinning; André Megarbane; Peter Meinecke; Robert K. Semple; Stephanie Spranger; Annick Toutain; Richard C. Trembath; Egbert Voss; Louise Wilson; Raoul Hennekam; Francis de Zegher; Helmuth-Günther Dörr; André Reis

doi:10.1126/science.1151174

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Mutations in the Pericentrin (PCNT) Gene Cause Primordial Dwarfism

Anita Rauch1,*,
Christian T. Thiel1,
Detlev Schindler2,
Ursula Wick1,
Yanick J. Crow3,
Arif B. Ekici1,
Anthonie J. van Essen4,
Timm O. Goecke5,
Lihadh Al-Gazali6,
Krystyna H. Chrzanowska7,
Christiane Zweier1,
Han G. Brunner8,
Kristin Becker9,
Cynthia J. Curry10,
Bruno Dallapiccola11,
Koenraad Devriendt12,
Arnd Dörfler13,
Esther Kinning14,
André Megarbane15,
Peter Meinecke16,
Robert K. Semple17,
Stephanie Spranger18,
Annick Toutain19,
Richard C. Trembath20,
Egbert Voss21,
Louise Wilson22,
Raoul Hennekam22,23,24,
Francis de Zegher25,
Helmuth-Günther Dörr26,
André Reis1

¹ Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
² Department of Human Genetics, University of Würzburg, Würzburg, Germany.
³ Leeds Institute of Molecular Medicine, St. James's University Hospital, Leeds, UK.
⁴ Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
⁵ Institut für Humangenetik und Anthropologie, Heinrich-Heine-Universität, Düsseldorf, Germany.
⁶ Faculty of Medicine, United Arab Emirates University, Al-Ain, UAE.
⁷ Department of Medical Genetics, the Children's Memorial Health Institute, Warsaw, Poland.
⁸ Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University, Nijmegen Medical Centre, Netherlands.
⁹ North Wales Clinical Genetics Service, Glan Clwyd Hospital, Rhyl, and Institute of Medical Genetics, University Hospital of Wales, Cardiff, UK.
¹⁰ Genetic Medicine Central California, Fresno, and University of California, San Francisco, CA, USA.
¹¹ IRCCS-CSS, San Giovanni Rotondo and CSS-Mendel Institute, Rome, and Department of Experimental Medicine and Pathology, University of Rome La Sapienza, Rome, Italy.
¹² Centre for Human-Genetics, University of Leuven, Leuven, Belgium.
¹³ Department of Neuroradiology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
¹⁴ Department of Clinical Genetics, Leicester Royal Infirmary, Leicester, UK.
¹⁵ Unité de Génétique Médicale, Faculté de Médecine, Université Saint-Joseph, Beirut, Lebanon.
¹⁶ Abteilung für Medizinische Genetik, Altonaer Kinderkrankenhaus, Hamburg, Germany.
¹⁷ Department of Clinical Biochemistry, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
¹⁸ Praxis fuer Humangenetik, Bremen, Germany.
¹⁹ Department of Genetics, Bretonneau University Hospital, Tours, France.
²⁰ Department of Medical and Molecular Genetics, School of Medicine, King's College London, UK.
²¹ Cnopf's Pediatric Hospital, Nuremberg, Germany.
²² Department of Clinical Genetics, Great Ormond Street Hospital for Children, London, UK.
²³ Clinical and Molecular Genetics Unit, Institute of Child Health, University College London, London, UK.
²⁴ Department of Paediatrics, University of Amsterdam, Amsterdam, Netherlands.
²⁵ Department of Woman and Child, University of Leuven, Leuven, Belgium.
²⁶ Department of Pediatrics and Adolescent Medicine, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.

↵* To whom correspondence should be addressed. E-mail: Anita.Rauch{at}humgenet.uni-erlangen.de

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Science 08 Feb 2008:
Vol. 319, Issue 5864, pp. 816-819
DOI: 10.1126/science.1151174

Anita Rauch

Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.

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Christian T. Thiel

Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.

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Detlev Schindler

Department of Human Genetics, University of Würzburg, Würzburg, Germany.

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Ursula Wick

Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.

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Yanick J. Crow

Leeds Institute of Molecular Medicine, St. James's University Hospital, Leeds, UK.

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Arif B. Ekici

Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.

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Anthonie J. van Essen

Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.

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Timm O. Goecke

Institut für Humangenetik und Anthropologie, Heinrich-Heine-Universität, Düsseldorf, Germany.

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Lihadh Al-Gazali

Faculty of Medicine, United Arab Emirates University, Al-Ain, UAE.

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Krystyna H. Chrzanowska

Department of Medical Genetics, the Children's Memorial Health Institute, Warsaw, Poland.

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Christiane Zweier

Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.

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Han G. Brunner

Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University, Nijmegen Medical Centre, Netherlands.

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Kristin Becker

North Wales Clinical Genetics Service, Glan Clwyd Hospital, Rhyl, and Institute of Medical Genetics, University Hospital of Wales, Cardiff, UK.

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Cynthia J. Curry

Genetic Medicine Central California, Fresno, and University of California, San Francisco, CA, USA.

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Bruno Dallapiccola

IRCCS-CSS, San Giovanni Rotondo and CSS-Mendel Institute, Rome, and Department of Experimental Medicine and Pathology, University of Rome La Sapienza, Rome, Italy.

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Koenraad Devriendt

Centre for Human-Genetics, University of Leuven, Leuven, Belgium.

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Arnd Dörfler

Department of Neuroradiology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.

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Esther Kinning

Department of Clinical Genetics, Leicester Royal Infirmary, Leicester, UK.

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André Megarbane

Unité de Génétique Médicale, Faculté de Médecine, Université Saint-Joseph, Beirut, Lebanon.

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Peter Meinecke

Abteilung für Medizinische Genetik, Altonaer Kinderkrankenhaus, Hamburg, Germany.

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Robert K. Semple

Department of Clinical Biochemistry, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.

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Stephanie Spranger

Praxis fuer Humangenetik, Bremen, Germany.

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Annick Toutain

Department of Genetics, Bretonneau University Hospital, Tours, France.

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Richard C. Trembath

Department of Medical and Molecular Genetics, School of Medicine, King's College London, UK.

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Egbert Voss

Cnopf's Pediatric Hospital, Nuremberg, Germany.

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Louise Wilson

Department of Clinical Genetics, Great Ormond Street Hospital for Children, London, UK.

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Raoul Hennekam

Department of Clinical Genetics, Great Ormond Street Hospital for Children, London, UK. Clinical and Molecular Genetics Unit, Institute of Child Health, University College London, London, UK. Department of Paediatrics, University of Amsterdam, Amsterdam, Netherlands.

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Francis de Zegher

Department of Woman and Child, University of Leuven, Leuven, Belgium.

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Helmuth-Günther Dörr

Department of Pediatrics and Adolescent Medicine, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.

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André Reis

Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.

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Abstract

Fundamental processes influencing human growth can be revealed by studying extreme short stature. Using genetic linkage analysis, we find that biallelic loss-of-function mutations in the centrosomal pericentrin (PCNT) gene on chromosome 21q22.3 cause microcephalic osteodysplastic primordial dwarfism type II (MOPD II) in 25 patients. Adults with this rare inherited condition have an average height of 100 centimeters and a brain size comparable to that of a 3-month-old baby, but are of near-normal intelligence. Absence of PCNT results in disorganized mitotic spindles and missegregation of chromosomes. Mutations in related genes are known to cause primary microcephaly (MCPH1, CDK5RAP2, ASPM, and CENPJ).

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In humans, an inherited condition with small brain size and near-normal intelligence is caused by mutations that disrupt chromosome separation during cell division.

Mutations in the Pericentrin (PCNT) Gene Cause Primordial Dwarfism

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